Certain halo and dihalo n-substituted salicylamides



United States Patent 3,455,940 CERTAIN HALO AND DIHALO N-SUBSTITUTEDSALICYLAMIDES Herbert C. Stecker, 1 Bridle Way, Ho-Ho-Kus, NJ. 07423 NoDrawing. Filed Dec. 7, 1965, Ser. No. 512,598 Int. Cl. C07c 103/26;C0711 31/44, 7/04 U.S. Cl. 260-295 Claims ABSTRACT OF THE DISCLOSURE Newcompounds, possessing high germicidal power and little or no tendency tocause discoloratioin in light, are claimed, having the general formula:

in which R is a methylene, ethylene or propylene group to which isattached 1 to 3 ring nuclei containing from 0 to 2 halogen atomsdirectly attached, said R containing not over 20 carbon atoms, and n isa numeral from 0 to 2, except when R is methylbenzene, in which case nis 1 to 2.

wherein R is a substituted methylene group to which is attachedhydrogen, alkyl, aryl, alkaryl, aralkyl or heterocyclic groups, said Rhaving a total of not over 20 carbon atoms,

X is hydrogen, halogen, trifluoromethyl, or nitro, and

n is a numeral from 0 to 2, except when R is methylbenzene, when n isthen 1 to 2.

The groups representing R may have polar substituents, such as halogen,hydroxy, silane, ethoxysilane, ether, amino, and the like. The methylenegroup may have attached to it one or two substituent groups, one or bothof which may be alkyl, aryl, alkylaryl, ethenol, and the like.

Of particular value for the purposes of the present invention, arecompounds in which R contains a methylene, ethylene or propylene groupto which is attached a single ring nucleus which may contain up to twohalogen atoms attached thereto. Another effective group of compoundsconsists of those in which R has a methylene, ethylene or propylenegroup to which is attached a radical containing a free amino group.

The compounds may he prepared by the following method, which is given asan example:

3,S-dibromosalicyl-N-4-chlorobenzylamide Molal quantities of3,5-dibromosalycylic acid are reacted in presence of phosphorustrichloride to produce 3,5-dibromosalicyl chloride. When reaction iscomplete, an equimolar amount of 4-chlorobenzylamine is added, and themixture is heated until hydrogen chloride fumes 3,455,940 Patented July15, 1969 cease to be evolved. This reaction is carried out in an inertsolvent or suspension agent, such as chlorobenzene. After reaction iscomplete, the product is isolated by evaporation of the solvent,suspending the residue in water, filtering, redissolving or suspendingthe filter cake in alcohol and re-filtering, using the lastprocedureth-ree times to insure the removal of byproducts and residue ofunreacted intermediates.

Table I lists a number of compounds of the present invention prepared inaccordance with the aforesaid process. Reacted with theparticularly-substituted salicyl chloride, are the following reactants,listed in the numerical order given in the table:

(I) 4-chlorobenzylamine.

(2) Benzylamine.

(3) Benzylamine.

(4) 4-chlorobenzylamine.

(5) Alpha-(l-aminoethyl)-p-hydroxybenzyl alcohol. (6) Ethanolamine.

(7) Propylamine.

(8) l-(beta aminoethyl)-2-imidazolidone.

(9) N-(2-aminoethyl) indole.

( 10) l-(B-aminoethyl)-2-methy1-2-imidazo1ine. (11) N-(2-aminoethyl)morpholine.

(12) N-(2-aminoethyl) piperazine.

(13) 2-(2-aminoethyl) pyridine.

(l4) N-(Z-aminoethyl) pyrrolidine.

( 15 4-aminomethyl-l-benzyl-4-phenylpiperidinc. (16) S-aminolevulinicacid.

(17) 2-aminomethylbenzimidazole.

(l8) Endo-2-amin0methylbicyclo (2.2.1) heptane. (19) Phenethylamine.

(20) 2,4-dichlorobenzylamine.

(21) 3,4-dichlorobenzylamine.

(22) O-chlorobenzylamine.

(23) p-Chlorobenzylamine.

(24) 2,4-dimethyl benz ylamine.

(25) p-Fluorobenzylamine.

m-Methylbenzylamine.

l-naphthalene methylamine.

4-aminomethylpyridine.

3-a'minornethylpyridine.

Z-aminomethylpyridine.

4-aminomethyl piperidine.

(32) 2-aminomethyl tetrahydropyran.

(33) 2-aminomethyl-3,4-dihydro-2H-pyran.

(34) N-(3-aminopropyl) diethanolamine.

(35 N- (Y-aminopropyl -N'-methylpiperazine.

(36) N-(3-aminopropyl) morpholine.

(37) N-(3-aminopropyl) 'piperidine.

(38) 3-aminopropyl triethoxysilane.

(39) S-benzyloxytryptamine.

(40) N,N'-bis-(3-aminopropyl) piperazine.

(41) N,N'-bis-( 3-aminopropyl) piperazine.

(42) 6-fluoro-alpha-methyltryptamine.

(43) Furfurylamine.

(44) Histamine.

(45) Homotryptamine.

(46) B-(3,4-methylenedioxyphenyl) isopropylamine.

(47) N-(4-picolyl) ethylenediamine.

(48) Piperonylamine.

(49) Tetrahydrofurfurylamine.

(50) n-Nonylamine.

(51) 1,6-hexanediamine.

(52) 1,6-hexanediamine.

(53) m-Xylylenediamine.

(54) rn-Xylylenediamine.

(55) 2-(p-tolyl) ethylamine.

(56) 1,4-bis-(aminomethyl) cyclohexane.

(57) 1,4bis(3,S-dibromosalicylaminomethyl) cyclohexane.

TABLE 1- 001111111100 Nitrogen M.I.C.',

.p.m No. X R 0010. Found st uureu 3,5-dibromo -oH,-c1 3.00 3.00 0.01

l 21 do OH|-Cl 3. 01 3.01 0.01

01 22 .-do -CH.@ 3.34 3.35 0.01

CH; 24 .05 OH|-CH1 3.30 3.30 0.02

25 4-01. -cH.-F 047 4.47 0.04

CH: 20 30101055001011.-- -OH 3. 05 3.04 0.03

27 4-01, -CHr-8 4.00 4.05 0.10

22 0-01. cm-OI 0. 40 0.44 0.10

20 5-bromo CH1C 0.12 0.12 0.10

31 54110111010 CH C NH1 0.23 21 0.02

o 32 CHr-U a. 88 3. 87 0.05

o 33 50111010 -CH1U 5. 2a 5.23 0. 05

2.4 35010151115 -CH:CHICHIN(CH,CH;OH): 0. 30 0.35 0. 05

/j 35 -05 --CH1-CHr-N NCH; 0.05 0.03 0.10

36 "do -CHr-CH:CHr-N b 6. 63 6. 61 0. 10

31 --do -CH1CH1CH;-N: 0. 07 0. 07 0.10

as .00 -CHr-CH;-CH1Si(0C:H1); 2.01 2.02 0.15

39 d0 CH2CH1 ""I C1110 5.14 5.13 0.10

40 d0 --CHr-CH:CH:N N-CHrCHr-CHr-NH: 8. 78 8.76 0.10

TABLE IContinued Nitrogen M.I.C., p.p.n1., No. X R 0010. Found S. aureus(|)H I! 41 3,5 dibromo -OH1CH:OH1N N-cm-om-om-NH-o- Br 7.41 1.39 0.02

l Br 1H3 42 "do CH:CH W F 5.96 5.95 0.02

43 1 --..do OHv-W 3.13 3.14 0.02

44 do --CHz-CH; 10.30 10.13 0.02

45 do --CH=-CH -CH, NH

40 10 -OH;OH 0 3. 00 3. 05 0.04

41 .410 -cH1-cH,-NH-cH,-O 9.19 9.11 0.03

0 4s ..do CH 3.26 3. 25 0. 03

49 .410 -CH|( I 3.10 3. 69 0.02

-CH,(CH1)1CHa 3. 33 3. 33 0. 05

OH;-(CH:)s-NH: 1. 11 1. 10 0. 05

OH (I? l 52 .1-.-do CH:(CH1)1NHC Br 4.11 4.11 0.02

53 .-do -CHr- CHs-NH: & 10 6.75 0.05

0H f I 54 .-do -0H Om-NH-C Br 4.04 4.05 0. 04

55 .do --CH1CH1 3.39 3.39 0.10

TABLE I--Cntinued Nitrogen M.I.C.

p.p.m., No. X R Cale. Found S. aureus 50 3,5-dibromo CH2' 0. 07 6.660.10

CHg-NH:

57 do -OH: O )H Br 4.01 4.00 0.05

ll orn-Nn-o Br F 58 ammo CHCHz-OH 8.82 8.80 0.01

59 -bromo C1CH1OH 4.83 4.34 0.01

H on r 60 5-chloro -(l3C(CH3)3 5. 47 5. 48 0.05

l Ill/CH2 02 AID 4 41 4. 41 0.15

CHrCH;

03 3,5-dlcl1lor0 --%(0H2).0H3 4.00 4.01 0.10

04. 3,5-dibromo -CHz--CH J 3.46 3.45 0.05

It will be noted that Table I lists, first, the numerical order of thecompounds. The second listing is the substituent X, which is thesubstituent in the salicyl portion of the molecule of the genericformula given. Absence of any listing indicates that the nucleus isunsubstituted. The third column of the table designates the portion R ofthe generic formula. The fourth and fifth columns of the table specifythe percentage of nitrogen as calculated and as actually found in thereaction product, which is the subject of the present invention.

The sixth column of the table specifies the germicidal effectiveness ofthe compound against S. aureus, as the minimum inhibitory concentration,in parts per million. This was determined as follows:

Ten milligrams of each compound were dissolved in 1000 ml. of nutrientbroth adjusted to pH 6.8. From each such dilution, ml. dilutions wereprepared in sterile broth varying in strength between 10 ppm. and 0.2p.p.m., utilizing tubes for each compound. Each dilution was inoculatedwith 0.1 ml. of a 24-hour-old broth culture of S. aureus, and all tubeswere read for density on a densitometer, and the values recorded. Acontrol broth was inoculated. All tubes were inoculated at 37 C. forexactly 24 hours. Following inoculation, all tubes were re-read in thedensitometer and, since growth of the organism creates turbidity, thehigher the densitometer reading, the greater the growth. A turbidometricreading equal to that of the control would indicate no activity of thecompound. A reading equal to that prior to incubation indicates activityof the compound. The above results show the concentration at whichincrease in densitometer reading was observed.

Compound 65, although not encompassed by the invention, is included forthe purpose of comparison, to show its germicidal ineffectiveness, whencompared to the compounds claimed herein.

The compounds of the present invention have been found effective againstmicro-organisms, such as bacteria, fungi, and the like, such as A.niger, E. coli, S. typhi, L. casei, S. clzoleraesuis, and the like.

One of the disadvantages of present phenolic germicides is theirtendency to discolor in the presence of light, particularly in presenceof soaps and on light colored fabrics and in cosmetics. Thisdiscoloration has been attributed to the phenolic group. Yet, attemptsto circumvent this coloration problem, while still retaining thephenolic hydroxyl group, have not proved successful. According to thepresent invention, it has been possible to product very effectivegermicides while retaining the phenolic salicyl group and amidestructure and yet inhibit discoloration in light thereby for areasonable period of time. The compounds of the present invention appearto accomplish this effect by reducing the possibility of formation ofdouble bonds thought to be responsible for the undesirable colordevelopment.

When the compounds of the present invention are incorporated ingermicidally-efiective amounts in soap or detergent compositions, suchas toilet bars, for example, a very high degree of effectiveness againstmicro-organisms is obtained. Furthermore, when the light-colored bar isexposed to sunlight, color development is considerably reduced orvirtually eliminated for a reasonably long period of time. When thepresent compounds are applied to White or light-colored textile fabrics,the same advantages are realized, thus minimizing the necessity of usingoptical bleaches or other artificial means for offsetting discoloration.

A further and very distinct advantage in employing the compounds of thepresent invention, particularly in contact with the skin, is the factthat, upon hydrolysis, they do not form aniline or substituted anilines,which have been found to produce methemoglobemia and other undesirablephysiological effects in some cases.

Table II lists experimental data obtained on the germicidaleffectiveness of the compounds of the present invention when applied tofabrics such as cotton, nylon and wool. The germicidal compounds weredissolved in 50% alcohol at a concentration of 0.10% with 0.02% of anonionic detergent (sold commercially under the tradename of IgepalCO-630). The test fabrics were immersed in the solution momentarily,after which they were dried and a disk thereof was placed on nutrientagar seeded with S. aureus and incubated at 37 C. for 24 hours.

TABLE II Zone of Inhibition, mm.

Germicide Cotton Nylon Wool 3,5-dibromosalicyl-N-4 chlorobenzylamide10.0 7. 5 11. 8,5-dibromosalicy1-N-phenethylamide 9. 7. 0 9. 55-iodosalicyl-N-2-aminomethyltetral0. 5 9. 0 11. 0

hydropyran. 4trifiuoromethylsalicyl-N--aminw 9. 0 8. 5 9. 5

methylpyridine. 3-5-diiodosalicyl-N-2-aminoethanol 12. 5 8. 5 12. 5

TABLE III Germicide: Zone of inhibition, mm.Salicyl-N-4-chlorobenzylamide 5.03,5-dibromosalicy1-N-4-aminomethyl-1-benzyl-4- phenylpiperidine 6.0S-bromosalicyl-N-Z-(Z-aminoethyl) pyridine 5.0

4-trifluoromethylsalicyl-N-4-fluorobenzylamide 5 .05-chlorosalicyI-N-Z-aminomethyl-3,4-dihydro-2H- pyran 5.53,5-dibromosalicyl piperonylamide 6.0Bis(3,5-dibromosalicyl)-1,6-hexanediamide 6.5

The skin substantivity (leaching) tests were conducted by applyingaqueous solutions containing 5.0% by weight of Ivory brand neutralwhite, high-grade, tallow toilet soap which, in turn, contained 0.5% byweight (based on the soap) of the germicidal compounds of the presentinvention to fresh calfskin, and self-injecting the treated skin toclear Water leaching for 3 minutes. The skin disks then were placed onnutrient agar seeded with S. aureus, and incubated at 37 C. for 24hours. All tests were conducted in triplicate. It will be noted fromTable III that the compounds exhibited a high degree of substantivity.

Further, white soap bars made with 0.5% of the aboveidentifiedgermicides of Table III showed little or no discoloration after exposureto sunlight when compared with soap bars containing the same a mount ofconventional phenolic germicides, exposed to the same light for the sameperiod.

The compounds of the present invention are useful in compositionscomprising germicidally inert material, i.e., relatively speaking. Forexample, some soaps and detergents possess a bactericidal action, butsuch action, relative to those of the compounds of the presentinvention, is weak and activity of the composition. In suchcompositions, the compounds of the present invention may be employed inconcentrations as low as 10 p.p.m., although, from a practical point ofview, it is desirable to use as much as 50 p.p.m. or 0.001% by weight,or 0.01%, and as much as 0.1%, or more. The term germicidal activityincludes inhibiting and killing action against bacteria, fungi andsimilar organisms.

Particularly useful compositions of the present invention are thosecomprising soaps and detergents, and especially toilet soaps or cosmeticdetergents in which the compounds of the present invention may beemployed in concentrations of 0.1% to 0.5 by weight, or even as much as1% or more. The term detergent employed herein will be used to includeall synthetic and natural cleansing compositions, including cationicdetergents, such as dimethyl stearamido-propyl-Z-hydroxy-ammoniumdihydrogen phosphate, anionic detergents such as commercial soaps, e.g.,alkali metal soaps of hydrolyzed natural or synthetic glycerides offatty and similar organic acids, e.g., sodium and potassium stearates oroleates, ampholytic detergents, such as sarcosine, non-ionic detergentssuch as polyoxpropylene polyoxethylene condensates, natural detergents,such as starches, vegetable gums, and the like, and mixtures thereof.The term soap employed herein is used in its popular or ordinarymeaning, Le, a cleansing composition prepared from an alkali metalcompound such as potassium or sodium hydroxide and a fat or fatty acid,both saturated and unsaturated.

One valuable use of the compounds of the present invention is the usethereof to sanitize fibrous material such as cotton gauze, dressings,textiles, paper pulp, and the like. They also serve as antiseptic agentswhen incorporated in plastic or rubber compositions, prior to moldinginto articles of commerce, such as baby rattles, gloves, food wrappersand the like.

I claim:

1. A compound having the formula:

o ONHRYm Xn in which: X is a halogen or trifiuoromethyl group, n is 1 or2,

R is a radical of the class consisting of benzyl, tetrahydropyranylmethyl, pyridyl methyl, and betahydroxyethyl,

Y is hydrogen, methyl, or chlorine, and

m is 0, 1, or 2.

13 14 2. N-(4-ha1obenzyl)-3,S-dihalo-salicy-lamide. FOREIGN PATENTS 3vS-halo, N-tetrahydropyranylmethyl-salicylamide. 5 5 1/1960 Belgium 4.3,5-dihalo, N-hydroxyethyl-salicylamide. 5. Trifiuoromethyl,N-pyridyl-4-methy1-salicylamide. HENRY JILES Pnmary Exammer 5 ALAN L.ROTMAN, Assistant Examiner References Cited UNITED STATES PATENTS252-106, 117, 152; 26( )247.2, 268, 294, 295.5, 309, 2,703,332 3/1955Rlehen et a1 309.2, 309.6, 326.13, 326.3, 332.2, 340.5, 345.7, 347.3,2,861,916 11/1958 Model et a1 260-559 10 448.8, 519, 559; 424-262, 263,266, 267, 274, 282, 283,

2,967,885 1/1961 Lamberti 260559 285, 324

